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2D nanomaterials assembled from sequence-defined molecules

Two dimensional (2D) nanomaterials have attracted broad interest owing to their unique physical and chemical properties with potential applications in electronics, chemistry, biology, medicine and pharmaceutics. Due to the current limitations of traditional 2D nanomaterials (e.g., graphene and graphene oxide) in tuning surface chemistry and compositions, 2D nanomaterials assembled from sequence-defined molecules (e.g., DNAs, proteins, peptides and peptoids) have recently been developed. They represent an emerging class of 2D nanomaterials with attractive physical and chemical properties. In this mini-review, we summarize the recent progress in the synthesis and applications of this type of sequence-defined 2D nanomaterials. The challenges and opportunities in this new field are also discussed.

2D nanomaterials↗

Controlled synthesis of highly-branched plasmonic gold nanoparticles through peptoid engineering

Inspired by peptide- and protein-controlled formation of hierarchical inorganic nanostructures in nature, herein we report the design of sequence-defined peptoids for biomimetic synthesis of flower-like gold nanosuperstruc-tures. We demonstrate that the peptoid-induced morphosyn-thesis of gold nanoflowers is sequence-dependent. By varying the hydrophobicity, number of carboxylate and amino groups, and side-chain positions of peptoids, we develop a rule of thumb for designing peptoids that yield gold nanoflowers. Through a combination of hyperspectral UV-Vis absorption micro-spectroscopy (H-UVVIS-AMS) and three-photon photoemission electron microscopy (TP-PEEM), we measured the plasmonic properties of individual nanoflowers. Whereas H-UVVIS-AMS experiments revealed well-defined plasmon resonances centered at ~528 nm, TP-PEEM measurements showed an unprecedented plasmonic enhancement as high as 105 for a single nanoflower. A com-bination of the unique plasmonic property and the high sta-bility endows the peptoid-engineered nanoflowers with po-tential applications in chemical and biological imaging. FY, YC, HJ and C-LC acknowledge support by the Materials Synthesis and Simulation Across Scales (MS3) Initiative, through the Laboratory Directed Research & Development (LDRD) fund at Pacific Northwest National Laboratory (PNNL). FY was also partially supported by fellowships from Shandong Provincial Education Association for International Exchanges. YG was supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences & Biosciences. PZE acknowledges support from the Laboratory Directed Research and Development Program through a Linus Pauling Fellowship at PNNL. PNNL is multi-program national laboratory operated for the Department of Energy by Battelle under Contracts No. DE-AC05-76RL01830. The authors are most grateful to Alan Joly and Wayne Hess (PNNL) for their support with the PEEM measurements and several useful discussions.

Yan, Feng↗

Bioinspired Peptoid Nanotubes for Targeted Tumor Cell Imaging and Chemo-Photodynamic Therapy

Substantial progress has been made in applying nanotubes in biomedical applications such as bioimaging and drug delivery due to their unique architecture, characterized by very large internal surface areas and high aspect ratios. Yet, the biomedical applications of organic nanotubes, especially for those assembled from sequence-defined molecules, are very uncommon. In our work, the synthesis of two new peptoid nanotubes (PepTs1 and PepTs2) is reported by using sequence-defined and ligand-tagged peptoids as building blocks. These nanotubes are highly robust due to sharing a similar structure to those of nontagged ones, and offer great potential to hold guest molecules for biomedical applications. The findings indicate that peptoid nanotubes loaded with doxorubicin drugs are promising candidates for targeted tumor cell imaging and chemo-photodynamic therapy.

60 APPLIED LIFE SCIENCES↗

Peptoid-Based Programmable 2D Nanomaterial Sensor for Selective and Sensitive Detection of H 2 S in Live Cells

During the past decades, a variety of two-dimensional (2D) nanosheets have been developed through supramolecular self-assembly. Among them, those assembled from sequence-defined molecules have received particularly attention because they enable a precise displaying of functional groups, including fluorescent dyes, within nanosheet surfaces. On the other hand, due to the fluorescence self-quenching, synthesis of organic 2D nanosheets exhibiting high fluorescence quantum yields is a significant challenge. Herein, we report the utilization of H 2 S-responsive probes as peptoid sidechains to design and synthesize crystalline 2D nanomembranes (2DNMs) as selective and sensitive H 2 S sensors. These 2DNM sensors exhibit a high quantum yield as a result of high crystallinity and tunable probe density. Compared with amorphous state of peptoid assembly and pre-assembled peptoid-probe conjugates, these crystalline 2DNM sensors exhibit a significantly strong fluorescence intensity and a high sensitivity (~ 0.36 nM). By sonication-cutting these 2DNM sensors into a colloidal form in aqueous solution, we further demonstrated the use of colloidal 2DNMs for detecting both exogenous and endogenous H 2 S inside cells or targeted cell organelles. As far as we know, this is the first example of using sequence-defined 2D nanomaterials for selective and sensitive detection of H 2 S. Because peptoids are biocompatible and peptoid-based 2DNMs are highly programmable, we expect that this new class of 2DNM sensors offer great potentials for detecting H 2 S and for biological applications.

2D nanomaterials↗

Programming Amphiphilic Peptoid Oligomers for Hierarchical Assembly and Inorganic Crystallization

Natural organisms make a wide variety of exquisitely complex, nano-, micro-, and macroscale structured materials in an energy-efficient and highly reproducible manner. During these processes, the information-carrying biomolecules (e.g., proteins, peptides, and carbohydrates) enable (1) hierarchical organization to assemble scaffold materials and execute high-level functions and (2) exquisite control over inorganic materials synthesis, generating biominerals whose properties are optimized for their functions. Inspired by nature, significant efforts have been devoted to developing functional materials that can rival those natural molecules by mimicking in vivo functions using engineered proteins, peptides, DNAs, sequence-defined synthetic molecules (e.g., peptoids), and other biomimetic polymers. Among them, peptoids, a new type of synthetic mimetics of peptides and proteins, have received particular attention because they combine the merits of both synthetic polymers (e.g., high chemical stability and efficient synthesis) and biomolecules (e.g., sequence programmability and biocompatibility). The lack of both chirality and hydrogen bonds in their backbone results in a highly designable peptoid-based system with reduced structural complexity and side chain-chemistry-dominated properties. Here in this Account, we present our recent efforts in this field by programming amphiphilic peptoid sequences for (1) the controlled self-assembly into different hierarchically structured nanomaterials with favorable properties and (2) manipulating inorganic (nano)crystal nucleation, growth, and assembly into superstructures. First, we designed a series of amphiphilic peptoids with controlled side chain chemistries that self-assembled into 1D highly stiff and dynamic nanotubes, 2D membrane-mimetic nanosheets, hexagonally patterned nanoribbons, and 3D nanoflowers. These crystalline nanostructures exhibited sequence-dependent properties and showed promise for different applications. The corresponding peptoid self-assembly pathways and mechanisms were also investigated by leveraging in situ atomic force microscopy studies and molecular dynamics simulations, which showed precise sequence dependency. Second, inspired by peptide- and protein-controlled formation of hierarchical inorganic nanostructures in nature, we developed peptoid-based biomimetic approaches for controlled synthesis of inorganic materials (e.g., noble metals and calcite), in which we took advantage of the substantial side chain chemistry of peptoids and investigated the relationship between the peptoid sequences and the morphology and growth kinetics of inorganic materials. For example, to overcome the challenges (e.g., complexity of protein- and peptide-folding, poor thermal and chemical stabilities) facing the area of protein- and peptide-controlled synthesis of inorganic materials, we recently reported the design of sequence-defined peptoids for controlled synthesis of highly branched plasmonic gold particles. Moreover, we developed a rule of thumb for designing peptoids that predictively enabled the morphological evolution from spherical to coral-shaped gold nanoparticles (NPs). With this Account, we hope to stimulate the research interest of chemists and materials scientists and promote the predictive synthesis of functional and robust materials through the design of sequence-defined synthetic molecules.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Insights into the Biomimetic Synthesis of 2D ZnO Nanomaterials through Peptoid Engineering

Achieving predictable biomimetic crystallization using sequence-defined synthetic molecules in mild conditions represents a long-standing challenge in materials synthesis. Herein we report a peptoid-based approach for biomimetic control over the formation of nanostructured ZnO materials in ambient aqueous conditions. A series of two-dimensional (2D) ZnO nanomaterials have been successfully obtained using amphiphilic peptoids with different numbers, ratios, and patterns of various hydrophilic and hydrophobic side chains. By investigating the relationship between peptoid hydrophobicity and the thickness of the resultant ZnO nanomaterials, we found the critical role of peptoid hydrophobicity in the peptoid-controlled ZnO formation. Our results suggest that tuning the hydrophobicity of peptoids can be used to moderate peptoid–ZnO surface interactions, thus controlling the formation of ultrathin (<2.5 nm) 2D ZnO nanomaterials. Here, the peptoid-controlled formation of ZnO nanomaterials was further investigated using ultrasmall-angle X-ray scattering (USAXS). Our work suggests a new approach to synthesizing 2D metal oxide nanomaterials using sequence-defined synthetic molecules.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Toward Computation-Guided Design of Tunable Organic-Inorganic CdS Quantum Dot Binary Superlattices

Combining the advantages of structural programmability in sequence-defined biomimetic molecules and the controllable packing geometry in nanoparticle superlattices, we demonstrate a self-assembled organic-inorganic superlattice whose structure can be altered with the slightest change in the sequence of the organic counterpart. Here, oleate-coated CdS quantum dots (QDs) form a square-packed superlattice with a 1:1 molar equivalence of a di-block amphiphilic peptoid (Nbrpe6Dig) in chloroform. In contrast, no apparent structure is observed in the organic solvent alone. Based on theoretical evidence, we show that the assembly is a binary superlattice where both the CdS QDs and the peptoids serve as building blocks and further predict a correlation between the superlattice structure and the peptoid sequence. The computationally guided prediction is validated by experiments where superlattice transformation is observed with modified peptoids. The mechanism identified in our work inspires new ways to control and tune organic-inorganic hybrid nanomaterial self-assembly.

Qi, Xin↗

Highly Bright and Photostable Two-Dimensional Nanomaterials Assembled from Sequence-Defined Peptoids

Free-standing two-dimensional (2D) organic nanomaterials are highly attractive for biological applications because of their unique structural properties and high biocompatibility. Herein, we designed and synthesized a new class of highly bright and photostable membrane-mimetic 2D nanosheets from sequence-defined peptoids. These nanosheets exhibited the high quantum yield and photostability as a result of the precise placement and ordering of dansyl dye molecules within crystalline nanosheets. We further showed the use of these nanosheets as biocompatible and programmable probes for live cell imaging and cell labeling. Furthermore, by programing these nanosheets with different surface charges, we achieved the enhanced lysosome escape of these nanosheets, showing their great potential as nanocarriers for the efficient intracellular delivery of macromolecular drugs.

2D nanomaterials↗

Single-Molecule Electron Transport in Peptoids

Peptoids are structural analogs of peptides in which side chains are appended to the backbone nitrogen rather than the α-carbon. The sequence-defined modularity of peptoids enables precise control over structure−function relationships, enabling applications in energy storage and biomedical materials. Despite recent progress, the role of sequence and conformation on electron transport in peptoid molecules is not fully understood. Here, we synthesize a library of peptoid oligomers and characterize their molecular electronic properties using the scanning tunneling microscope-break junction (STM-BJ) technique. Our results show well-defined electron transport behavior for peptoid sequences containing aromatic side groups lacking hydrogen bonds (H-bonds) and without chemical substitutions at the N−C α position. This behavior fundamentally differs from electron transport in peptides, where H-bond interactions give rise to higher conductance states. All-atom molecular dynamics (MD) simulations are used to understand the conformational heterogeneity of peptoids, and molecular conformations obtained from MD simulations are used in quantum mechanical calculations based on the nonequilibrium Green’s function−density functional theory (NEGF-DFT) formalism. In all cases, computational results are in reasonable qualitative agreement with experiments. Our work demonstrates that the conductance behavior of peptoids depends on monomer identity, including side-chain aromaticity and substitution at the N−C α position. Overall, this work provides new insights into the structure−function relationships governing electron transport in peptoid-based materials and establishes design rules for peptoid-based molecular junctions.

Charge transport↗

Compact Peptoid Molecular Brushes for Nanoparticle Stabilization

Controlling the interfaces and interactions of colloidal nanoparticles (NPs) via tethered molecular moieties is crucial for NP applications in engineered nanomaterials, optics, catalysis, and nanomedicine. Despite a broad range of molecular types explored, there is a need for a flexible approach to rationally vary the chemistry and structure of these interfacial molecules for controlling NP stability in diverse environments, while maintaining a small size of the NP molecular shell. Here, we demonstrate that low-molecular-weight, bifunctional comb-shaped, and sequence-defined peptoids can effectively stabilize gold NPs (AuNPs). The generality of this robust functionalization strategy was also demonstrated by coating of silver, platinum, and iron oxide NPs with designed peptoids. Each peptoid (PE) is designed with varied arrangements of a multivalent AuNP-binding domain and a solvation domain consisting of oligo-ethylene glycol (EG) branches. Among designs, a peptoid (PE5) with a diblock structure is demonstrated to provide a superior nanocolloidal stability in diverse aqueous solutions while forming a compact shell (similar to 1.5 nm) on the AuNP surface. We demonstrate by experiments and molecular dynamics simulations that PE5-coated AuNPs (PE5/AuNPs) are stable in select organic solvents owing to the strong PE5 (amine)-Au binding and solubility of the oligo-EG motifs. At the vapor-aqueous interface, we show that PE5/AuNPs remain stable and can self-assemble into ordered 2D lattices. The NP films exhibit strong near-field plasmonic coupling when transferred to solid substrates.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Functional Biomimetic Polymers with Antimicrobial Activity

At PNNL, we have developed a completely new class of synthetic biomimetic sequence-defined polymers based on triazine chemistry, which we call TZPs. PNNL's new polymers offer the opportunity to achieve similar functions to natural macromolecules; specifically we designed and synthesized a diversity of test molecules for antimicrobial activity. Antimicrobial activity against a variety of wild type and drug resistant pathogens was found.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Sequence-Defined Nanotubes Assembled from IR780-Conjugated Peptoids for Chemophototherapy of Malignant Glioma

Near-infrared (NIR) laser-induced phototherapy through NIR agents has demonstrated the great potential for cancer therapy. However, insufficient tumor killing due to the nonuniform heat or cytotoxic singlet oxygen ( 1 O 2 ) distribution over tumors from phototherapy results in tumor recurrence and inferior outcomes. To achieve high tumor killing efficacy, one of the solutions is to employ the combinational treatment of phototherapy with other modalities, especially with chemotherapeutic agents. In this paper, a simple and effective multimodal therapeutic system was designed via combining chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) to achieve the polytherapy of malignant glioma which is one of the most aggressive tumors in the brain. IR-780 (IR780) dye-labeled tube-forming peptoids (PepIR) were synthesized and self-assembled into crystalline nanotubes (PepIR nanotubes). These PepIR nanotubes showed an excellent efficacy for PDT/PTT because the IR780 photosensitizers were effectively packed and separated from each other within crystalline nanotubes by tuning IR780 density; thus, a self-quenching of these IR780 molecules was significantly reduced. Moreover, the efficient DOX loading achieved due to the nanotube large surface area contributed to an efficient and synergistic chemotherapy against glioma cells. Given the unique properties of peptoids and peptoid nanotubes, we believe that the developed multimodal DOX-loaded PepIR nanotubes in this work offer great promises for future glioma therapy in clinic.

60 APPLIED LIFE SCIENCES↗

Tuning crystallization pathways through sequence engineering of biomimetic polymers

Two-step nucleation pathways in which disordered, amorphous, or dense liquid states precede the appearance of crystalline phases have been reported for a wide range of materials, but the dynamics of such pathways are poorly understood. Moreover, whether these pathways are general features of crystallizing systems or a consequence of system-specific structural details that select for direct versus two-step processes is unknown. Using atomic force microscopy to directly observe crystallization of sequence-defined polymers, we show that crystallization pathways are indeed sequence dependent. When a short hydrophobic region is added to a sequence that directly forms crystalline particles, crystallization instead follows a two-step pathway that begins with the creation of disordered clusters of 10–20 molecules and is characterized by highly non-linear crystallization kinetics in which clusters transform into ordered structures that then enter the growth phase. The results shed new light on non-classical crystallization mechanisms and have implications for the design of self-assembling polymer systems.

36 MATERIALS SCIENCE↗

Sequence-defined Pareto frontier of a copolymer structure

The correlations between the sequence of monomers in a macromolecule and its three-dimensional (3D) structure is a grand challenge in polymer science. The properties and functions of macromolecules depend on their 3D shape that has appeared to be dictated by their monomer sequence. However, the progress towards understanding the sequence–structure-property correlations and their utilization in materials engineering are slow because it is almost impossible to characterize an astronomically large number of possible sequences of a copolymer using traditional experimental and simulation methods. To address this problem, here, we combine evolutionary computing and coarse-grained molecular dynamics (CGMD) simulation and study the sequence-structure correlations of a model AB-type copolymer in a solution and assess the impact of sequence on the packing density in its bulk phase. The CGMD-based evolutionary algorithm (EA) screens the sequence space of a single chain copolymer efficiently and identifies a wide range of single-molecule structures including extremal radii of gyration. The data are utilized to estimate the Pareto front of the structure-space of a binary copolymer as a function of its composition. The monomer packings in single-molecule solution phase and multimolecular bulk phase are found to be identical. Finally, this work highlights the opportunities of sequence-specific control of macromolecular structure for designing target materials.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗